biostudies-literatureNull MNHGRI NIH HHS680-691https://www.ebi.ac.uk/biostudies/studies/S-EPMC9069075biostudies-literatureUnknown109(4)Identification of rare-variant associations is crucial to full characterization of the genetic architecture of complex traits and diseases. Essential in this process is the evaluation of novel methods in simulated data that mirror the distribution of rare variants and haplotype structure in real data. Additionally, importing real-variant annotation enables in silico comparison of methods, such as rare-variant association tests and polygenic scoring methods, that focus on putative causal variants. Existing simulation methods are either unable to employ real-variant annotation or severely under- or overestimate the number of singletons and doubletons, thereby reducing the ability to generalize simulation results to real studies. We present RAREsim, a flexible and accurate rare-variant simulaAmerican journal of human geneticsRAREsim: A simulation method for very rare genetic variants.PMC9069075U01 HG009080R35 HG011293Dupuis JHendricks AENull MSheinidashtegol PLayer RMGignoux CRfalseRAREsim: A simulation method for very rare genetic variants.Identification of rare-variant associations is crucial to full characterization of the genetic architecture of complex traits and diseases. Essential in this process is the evaluation of novel methods in simulated data that mirror the distribution of rare variants and haplotype structure in real data. Additionally, importing real-variant annotation enables in silico comparison of methods, such as rare-variant association tests and polygenic scoring methods, that focus on putative causal variants. Existing simulation methods are either unable to employ real-variant annotation or severely under- or overestimate the number of singletons and doubletons, thereby reducing the ability to generalize simulation results to real studies. We present RAREsim, a flexible and accurate rare-variant simula2022-01-01T00:00:00Z2022 Apr2025-04-19T17:36:34.582Z2025-04-19T17:36:34.582ZS-EPMC90690753529891910.1016/j.ajhg.2022.02.009